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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons., (© 2021. The Author(s).)

Objective: The Ljubljana ALS Centre, established in 2002, is the only tertiary center for amyotrophic lateral sclerosis (ALS) in Slovenia. The aim of our study was to evaluate the impact of therapeutic interventions and improvements in the multidisciplinary care on the survival of our patients. Methods: All patients diagnosed with ALS at our center during years 2003-2005 (early group) and 2011-2012 (late group) were included in this retrospective cohort study ( n  = 124). Kaplan-Meier survival analysis and multiple regression analysis with Cox proportional hazards model were performed to compare survival and to evaluate the differences between the two cohorts. Results: Median survival from the time of diagnosis was 13.0 (95% CI 10.2-15.8) months in the early group and 21.8 (95% CI 17.2-26.4) months in the late group ( p  = 0.005). In the Cox proportional hazards analysis, the late group of patients was associated with better survival independently of all other prognostic factors (hazard ratio (HR)=0.51, 95% CI = 0.32-0.81, p  = 0.004). Survival was also associated with patients' age, use of noninvasive ventilation (NIV) and gastrostomy. The model fit significantly improved when the interaction between the NIV use and the observed time period was added to the model (HR = 0.34, 95% CI = 0.12-0.96, p  = 0.041). Conclusions: Our findings suggest that improvements in the multidisciplinary care were beneficial for survival of our patients with ALS. The survival benefit in the late group of our patients could be partially explained by the improvements in the NIV use at our center.

Amyotrophic lateral sclerosis is a late-onset disorder primarily affecting motor neurons and leading to progressive and lethal skeletal muscle atrophy. Small RNAs, including microRNAs (miRNAs), can serve as important regulators of gene expression and can act both globally and in a tissue-/cell-type-specific manner. In muscle, miRNAs called myomiRs govern important processes and are deregulated in various disorders. Several myomiRs have shown promise for therapeutic use in cellular and animal models of ALS; however, the exact miRNA species differentially expressed in muscle tissue of ALS patients remain unknown. Following small RNA-Seq, we compared the expression of small RNAs in muscle tissue of ALS patients and healthy age-matched controls. The identified snoRNAs, mtRNAs and other small RNAs provide possible molecular links between insulin signaling and ALS. Furthermore, the identified miRNAs are predicted to target proteins that are involved in both normal processes and various muscle disorders and indicate muscle tissue is undergoing active reinnervation/compensatory attempts thus providing targets for further research and therapy development in ALS.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Amyotrophic lateral sclerosis (ALS) is a complex fatal neurodegenerative disease characterized by progressive degeneration and loss of upper motor neurons in the cerebral cortex and lower motor neurons in brainstem and spinal cord. We established the frequencies of mutations in 4 major ALS-associated genes, SOD1, TARDBP, FUS, and C9ORF72 in a representative cohort of 85 Slovenian patients with sporadic form of ALS. Pathogenic massive hexanucleotide repeat expansion mutation in C9ORF72 was detected in 5.9% of patients and was the most common cause of the disease. In the remaining 3 genes, we identified 4 changes in 3 patients, p.Val14Met in SOD1, silent mutation p.Arg522Arg in FUS, and p.Gly93Cys in SOD1 together with a novel synonymous variant c.990A>G (p.Leu330Leu) in TARDBP gene, respectively. This study represents the first genetic screening of major causative genes for ALS in a cohort of sporadic ALS patients from Slovenia and is according to our knowledge the first such study in Slavic population. Overall, we genetically characterized 8.2% sporadic ALS patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: This study explored event-related desynchronization (ERD) and synchronization (ERS) in amyotrophic lateral sclerosis (ALS) to quantify cortical sensorimotor processes during volitional movements. We furthermore compared ERD/ERS measures with clinical scores and movement-related cortical potential (MRCP) amplitudes., Methods: Electroencephalograms were recorded while 21 ALS patients and 19 controls performed two self-paced motor tasks: sniffing and right index finger flexion. Based on Wavelet analysis the alpha and beta frequency bands were selected for subsequent evaluation., Results: Patients generated significantly smaller resting alpha spectral power density (SPD) and smaller beta ERD compared to controls. Additionally patients exhibited merely unilateral post-movement ERS (beta rebound) whereas this phenomenon was bilateral in controls. ERD/ERS amplitudes did not correlate with corresponding MRCPs for either patients or controls., Conclusions: The smaller resting alpha SPD and beta ERD and asymmetrical appearance of beta ERS in patients compared to controls could be the result of pyramidal cell degeneration and/or corpus callosum involvement in ALS., Significance: These results support the notion of reduced movement preparation in ALS involving also areas outside the motor cortex. Furthermore post-movement cortical inhibition seems to be impaired in ALS. ERD/ERS and MRCP are found to be independent measures of cortical motor functions in ALS., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Our aim was to investigate changes in movement-related cortical potentials (MRCPs) in ALS patients with different degrees of upper motor neuron (UMN) involvement. Since respiratory failure is the main cause of death in ALS, changes in inspiratory-related (sniffing) potentials were studied in addition to finger-flexion-related potentials. Subjects (21 ALS, 19 controls) performed two self-paced motor tasks while their EEGs were recorded. The first task required flexions of the right index finger and the second, brisk nasal inspirations. The early (BP1), late (BP2) and motor potential (MP) components of MRCPs were evaluated. Results showed that patients generated higher MRCPs than controls. However, this effect was most significant in the subgroup of patients with low UMN burden (LUB). The high UMN burden (HUB) subgroup did not differ from controls, but had significantly lower MP amplitudes than the LUB subgroup. Progressive UMN deterioration was associated with an initial increase, followed by a later decrease, in MP amplitudes in ALS. In conclusion, the increased MRCPs in LUB compared to HUB patients indicate different processes of ALS pathophysiology that force opposing changes in MRCP amplitudes.

Objective: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by degeneration of the upper and lower motor neurons. Each voluntary movement, including inspiration, is preceded by movement-related cortical potential (MRCP) that can be recorded from the scalp. MRCPs of ALS patients with severe upper motor neuron involvement are smaller. Our aim was to explore whether the inspiratory-(sniffing)-related cortical potentials (SRCPs) and index-finger-flexion MRCPs (FFRCPs) can be used as markers of cortical involvement in ALS., Methods: Thirteen ALS patients and 15 healthy volunteers were assessed for their hand dexterity and strength, respiratory function, speech capacity, spasticity, electromyographic parameters and functional rating scales. EEG was recorded during self-paced sniffing and the right index finger flexion. The MRCP amplitudes were assessed at the relevant electrode positions., Results: No statistically significant difference was found between the MRCP amplitudes of the ALS patients and the control subjects. However, patients with more severely affected upper limb functions generated smaller FFRCPs and those with more affected respiratory functions generated smaller SRCPs. Excessively high FFRCPs were associated with better while excessively low FFRCPs with worse scores on some of the clinical measures of the upper limb function., Conclusion: Our preliminary results demonstrate that it is feasible to record SRCP in ALS patients, which combined with FFRCP, may be useful to determine the spectrum of motor control changes in this population., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The study aimed to evaluate the nature and extent of executive deficits in nondemented amyotrophic lateral sclerosis (ALS) patients. A total of 22 ALS patients and 21 matched controls were compared on standard neuropsychological tests of executive functions with appropriate control for motor impairment and on an ecologically valid motor-free test of executive functions, the Medication Scheduling Task (MST). Our results show that motor dysfunction can present a significant confound when using standard neuropsychological measures; however, even when accounting for motor disabilities, ALS patients show a robust pattern of cognitive dysfunctions. Additionally, MST was shown to be a sensitive measure of cognitive impairment, providing an important insight into cognitive processes relevant for patients' daily living.

Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, Ljubljana, Slovenia Genetic studies have managed to explain many cases of familial amyotrophic lateral sclerosis (ALS) through mutations in several genes. However, the cause of a majority of sporadic cases remains unknown. Recently, epigenetics, especially miRNA studies, show some promising aspects. We aimed to evaluate the differential expression of 10 miRNAs, including miR-9, miR-338, miR-638, miR-663a, miR-124a, miR-143, miR-451a,miR-132,miR-206, and let-7b, for which some connection to ALS was shown previously in ALS culture cells, animalmodels or patients, and in threemiRNA host genes, including C1orf61 (miR-9), AATK (miR-338), and DNM2 (miR-638), in leukocyte samples of 84 patients with sporadic ALS. We observed significant aberrant dysregulation across our patient cohort for miR-124a, miR-206, miR-9, let-7b, and miR-638. Since we did not use neurological controls we cannot rule out that the revealed differences in expression of investigated miRNAs are specific for ALS. Nevertheless, the group of these five miRNAs is worth of additional research in leukocytes of larger cohorts from different populations in order to verify their potential association to ALS disease. We also detected a significant up-regulation of the AAKT gene and down-regulation of the DNM2 gene, and thus, for the first time, we connected these with sporadic ALS cases. These findings open up new research toward miRNAs as diagnostic biomarkers and epigenetic processes involved in ALS. The detected significant deregulation of AAKT and DNM2 in sporadic ALS also represents an interesting finding. The DNM2 gene was previously found to bemutated in Charcot-Marie-Tooth neuropathy-type CMT2Mand centronuclear myopathy (CNM). In addition, as recent studies connected AATK and frontotemporal dementia (FTD) and DNM2 and hereditary spastic paraplegia (HSP), these two genes together with our results genetically connect, at least in part, five diseases, including FTD, HSP, Charcot-Marie-Tooth (type CMT2M), CNM, and ALS, thus opening future research toward a better understanding of the cell biology involved in these partly overlapping pathologies. [ABSTRACT FROM AUTHOR]